Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). KS remains as a dominant cancer in AIDS patients despite highly active anti- retroviral therapy. KS development is closely associated with extensive angiogenesis and inflammation. Understanding the molecular basis of KSHV-induced angiogenesis and inflammation could provide insights into the mechanism of KSHV-induced pathogenesis, and serve as the basis for developing novel intervention approaches for KSHV-related malignancies. In the current funding period, we have made significant progresses toward this goal. We have shown that KSHV infection promotes angiogenesis, inflammation and cell invasion. Furthermore, we have shown that the immune complement system is activated in human KS tumors, in tumors of a novel model of KHSV-induced tumorigenesis, and in latent KSHV-infected endothelial cells. While the complement system is the host first line of defense against infections, abnormal activation of the system often results in pathological conditions. Indeed, our preliminary results have shown that KSHV activation of the complement system promotes cell growth and survival, and induces angiogenesis. The objective of this renewal application is to further dissect the molecular mechanism by which complement mediates KSHV-induced angiogenesis and tumorigenesis, and to explore therapeutic application of targeting the complement system for inhibiting KS development. The central hypothesis is that KSHV activation of the complement system promotes angiogenesis contributing to KSHV-induced tumorigenesis, and as a result, targeting the complement system can inhibit the development of KSHV-induced malignancies. We have in vitro infection models and reverse genetics systems that are uniquely suited for determining the outcomes of KSHV activation of the complement system and delineating the underlying mechanism. Furthermore, we have recently developed a novel model of KSHV-induced tumorigenesis that is particularly useful for preclinical testing of novel agents targeting KSHV and KS development. We will test the hypothesis by delineating the mechanism by which KSHV activates the complement system during latency (Aim 1), determining the mechanisms by which complement mediates KSHV-induced malignant cell growth, angiogenesis and inflammation (Aim 2), and exploring the therapeutic application of targeting complement in models of KSHV- induced tumorigenesis (Aim 3). The proposed project is highly innovative because this is the first description of viral hijacking of the complement system in KSHV persistent infection. It will define a novel mechanism of KSHV induction of angiogenesis and inflammation. It is highly significant as it will define the molecular mechanism of KSHV hijacking of the complement system, and identify novel intervention targets for KSHV- induced malignancies. The mechanisms identified from these studies could also be applied to other persistent infections and cancers.